I. Leontyev

The energetics of water molecules in proteins is studied using the water placement software Dowser. We compared the water position predictions for 14 high-resolution crystal structures of oligopeptide-binding protein (OppA) containing a large number of resolved internal water molecules. From the analysis of the outputs of Dowser with variable parameters and comparison with experimental X-ray data, we derived an estimate of the average dipole moment of water molecules located in the internal cavities of the protein and their binding energies. The water parameters thus obtained from the experimental data are then analyzed within the framework of charge-scaling theory developed recently by this group; the parameters are shown to be in good agreement with the predictions that the theory makes for the dipole moment in a protein environment. The water dipole in the protein environment is found to be much different from that in the bulk and in such models as SPC or TIPnP. The role of charg...

ABSTRACT We have studied stress effects in heteroepitaxial (Ba0.7Sr0.3)TiO3 thin films deposited by rf sputtering on (0 0 1) MgO substrates. By varying the deposition conditions, three-dimensional (3D) nucleation growth and layer-by-layer growth mechanisms were realized. X-ray diffraction (XRD) measurements revealed that tetragonal distortion and Curie temperature (Tc) depend on the growth mechanism. The frequency of the E(TO) soft mode in the polarized Raman spectra correlated with the value of two-dimensional stress, determined from XRD experiments. Temperature-dependent lattice parameters and Raman spectra revealed an upward shift of the Curie temperature. Two-dimensional compressive stress was found to be larger in the film grown by the 3D nucleation mechanism.

Electronic polarizability is an important factor in molecular interactions. In the conventional force fields such as AMBER or CHARMM, however, there is inconsistency in how the effect of electronic dielectric screening of Coulombic interactions, inherent for the condensed phase media, is treated. Namely, the screening appears to be accounted for via effective charges only for neutral moieties, whereas the charged residues are treated as if they were in vacuum. As a result, the electrostatic interactions between ionized groups are exaggerated in molecular simulations by the factor of about 2. The discussed here MDEC (Molecular Dynamics in Electronic Continuum) model provides a theoretical framework for modification of the standard non-polarizable force fields to make them consistent with the idea of uniform electronic screening of partial atomic charges. The present theory states that the charges of ionized groups and ions should be scaled; i.e. reduced by a factor of about 0.7. In several examples, including the interaction between Na (+) ions, which is of interest for ion-channel simulations, and the dynamics of an important salt-bride in Cytochrome c Oxidase, we compared the standard non-polarizable MD simulations with MDEC simulations, and demonstrated that MDEC charge scaling procedure results in more accurate interactions. The inclusion of electronic screening for charged moieties is shown to result in significant changes in protein dynamics and can give rise to new qualitative results compared with the traditional non-polarizable force fields simulations.

Employing the continuum dielectric model for electronic polarizability, we have developed a new consistent procedure for parameterization of the effective nonpolarizable potential of liquid water. The model explains the striking difference between the value of water dipole moment μ~3D reported in recent ab initio and experimental studies with the value μ (eff) ~2.3D typically used in the empirical potentials, such as TIP3P or SPC/E. It is shown that the consistency of the parameterization scheme can be achieved if the magnitude of the effective dipole of water is understood as a scaled value [Formula: see text], where ε el =1.78 is the electronic (high-frequency) dielectric constant of water, and a new electronic polarization energy term, missing in the previous theories, is included. The new term is evaluated by using Kirkwood - Onsager theory. The new scheme is fully consistent with experimental data on enthalpy of vaporization, density, diffusion coefficient, and static dielectric constant. The new theoretical framework provides important insights into the nature of the effective parameters, which is crucial when the computational models of liquid water are used for simulations in different environments, such as proteins, or for interaction with solutes.

We have studied a charge-insertion process that models the deprotonation of a histidine side chain in the active site of cytochrome c oxidase (CcO) using both the continuum electrostatic calculations and the microscopic simulations. The group of interest is a ligand to Cu(B) center of CcO, which has been previously suggested to play the role of the proton pumping element in the enzyme; the group is located near a large internal water cavity in the protein. Using the nonpolarizable Amber-99 force field in molecular dynamics (MD) simulations, we have calculated the nuclear part of the reaction-field energy of charging of the His group and combined it with the electronic part, which we estimated in terms of the electronic continuum (EC) model, to obtain the total reaction-field energy of charging. The total free energy obtained in this MDEC approach was then compared with that calculated using pure continuum electrostatic model with variable dielectric parameters. The dielectric constant for the "dry" protein and that of the internal water cavity of CcO were determined as those parameters that provide best agreement between the continuum and microscopic MDEC model. The nuclear (MD) polarization alone (without electronic part) of a dry protein was found to correspond to an unphysically low dielectric constant of only about 1.3, whereas the inclusion of electronic polarizability increases the protein dielectric constant to 2.6-2.8. A detailed analysis is presented as to how the protein structure should be selected for the continuum calculations, as well as which probe and atomic radii should be used for cavity definition. The dielectric constant of the internal water cavity was found to be 80 or even higher using "standard" parameters of water probe radius, 1.4 A, and protein atomic radii from the MD force field for cavity description; such high values are ascribed to the fact that the standard procedure produces unphysically small cavities. Using x-ray data for internal water in CcO, we have explored optimization of the parameters and the algorithm of cavity description. For Amber radii, the optimal probe size was found to be 1.25 A; the dielectric of water cavity in this case is in the range of 10-16. The most satisfactory cavity description, however, was achieved with ProtOr atomic radii, while keeping the probe radius to be standard 1.4 A. In this case, the value of cavity dielectric constant was found to be in the range of 3-6. The obtained results are discussed in the context of recent calculations and experimental measurements of dielectric properties of proteins.

A simple model for accounting for electronic polarization in molecular dynamics (MD) simulations is discussed. In this model, called molecular dynamics electronic continuum (MDEC), the electronic polarization is treated explicitly in terms of the electronic continuum (EC) approximation, while the nuclear dynamics is described with a fixed-charge force field. In such a force-field all atomic charges are scaled to reflect the screening effect by the electronic continuum. The MDEC model is rather similar but not equivalent to the standard nonpolarizable force-fields; the differences are discussed. Of our particular interest is the calculation of the electrostatic part of solvation energy using standard nonpolarizable MD simulations. In a low-dielectric environment, such as protein, the standard MD approach produces qualitatively wrong results. The difficulty is in mistreatment of the electronic polarizability. We show how the results can be much improved using the MDEC approach. We also show how the dielectric constant of the medium obtained in a MD simulation with nonpolarizable force-field is related to the static (total) dielectric constant, which includes both the nuclear and electronic relaxation effects. Using the MDEC model, we discuss recent calculations of dielectric constants of alcohols and alkanes, and show that the MDEC results are comparable with those obtained with the polarizable Drude oscillator model. The applicability of the method to calculations of dielectric properties of proteins is discussed.